Approximately 100 million people worldwide suffer from type II diabetes, which is typically characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, such as retinopathy, neuropathy, nephropathy and macrovascular disease.
Accordingly, hepatic glucose production is an important potential target for type II diabetes therapy. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Particularly, glycogenolysis is catalyzed in the liver, muscle and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. Prior studies suggest that glycogenolysis may make an important contribution to hepatic glucose output in type II diabetes. See, for example, WO 96/39384; WO 96/39385; EP 978279; Proc. Natl. Acad. Sci. USA 1998, 95, 1776–1781; J. Med. Chem. 1998, 41, 2934–2938; Exp. Opin. Invest. Drugs 2001, 10, 439–454; EP 1136071; and WO 03/37864. Thus, glycogen phosphorylase inhibitors are believed to be useful therapeutic agents for treating type II diabetes and delaying the onset of diabetic complications by decreasing hepatic glucose production and lowering glycemia, while providing minimal risk of hypoglycemia and weight gain. See Id.
Based on the aforementioned references and additional references, for example, WO 96/39384; WO 96/39385; WO 00/47206; U.S. Pat. No. 5,952,322; WO 99/43663; EP 1088824; US 2001/0046958; EP 1149580; WO 01/23347; EP 1177791; WO 99/26659; U.S. Pat. No. 5,998,463; EP 1136071; US 2004/0002495 and EP 1041068, it is believed that glycogen phosphorylase inhibitors may be useful in treating, preventing or slowing the progression of diseases such as diabetes and related conditions (such as hyperglycemia, impaired glucose tolerance, insulin resistance and hyperinsulinemia), the microvascular complications associated with diabetes (such as retinopathy, neuropathy, nephropathy and delayed wound healing), the macrovascular complications associated with diabetes (cardiovascular diseases such as atherosclerosis, abnormal heart function, myocardial ischemia and stroke), as well as Metabolic Syndrome and its component conditions including hypertension, obesity and dislipidemia (including hypertriglyceridemia, hypercholesterolemia and low HDL), and other maladies such as non-cardiac ischemia, infection and cancer.